Protein misfolding represents a fundamental problem associated with aging and age-associated degenerative disease. The actions of several classes of stress-inducible molecular chaperones are required to resolve such dilemmas. Expression of inducible chaperones is often regulated by the transcription factor, heat shock factor 1 (HSF-1). HSF-1 is required for lifespan extension in the nematode Caenorhabditis elegans, particularly in long-lived animals with mutations in the insulin-like signaling (ILS) pathway. The goal of this proposal is to understand mechanistically how regulation of HSF-1 activity and chaperone expression by ILS occurs. Our hypothesis is that C. elegans HSF-1 regulates inducible molecular chaperone expression to provide stress resistance and promote longevity through interactions with multiple components of the ILS pathway. This hypothesis will be explored in the following ways: (1) by examining direct regulation of HSF-1 by kinases in the ILS pathway, and (2) by studying the co-regulation of multiple molecular chaperone genes by HSF-1, DAF-16 (another transcription factor regulated by ILS), and BAR-1 (a DAF-16 co-regulator). This approach will contribute significantly to elucidating the overall function of HSF-1 in lifespan extension. [unreadable] [unreadable] [unreadable]